Parkinson's disease is a debilitating neuropathology associated with the loss of nigrostriatal dopaminergic neurons. Interestingly, cardinal symptoms of resting tremor, rigidity and akinesia do not occur until denervation is extensive. Animal studies indicate that motor function is normalized by the maintenance of dopaminergic tone, the ambient concentration of dopamine in brain extracellular fluid. How dopaminergic tone is maintained despite the near complete loss of dopaminergic neurons has been the focus of previous work by PI Garris. In this project, efforts will be directed at examining, in the severely dopamine-depleted striatum, why dopaminergic signaling fails and how L-DOPA acts. L-DOPA is the primary medication used to treat Parkinson's disease today. Voltammetric microsensor experiments will be performed in an animal model, the 6-hydroxydopamine-lesioned rat. These probes, monitoring dopamine with millisecond temporal and micron spatial resolution, permit direct assessment of the central mechanisms of extracellular dopaminergic neurotransmission, release, uptake and diffusion. Specific Aim 1 characterizes compensatory adaptation of DA release and uptake, and the relationship between DA diffusion, synthesis and metabolism. The goal is a more comprehensive view of dopaminergic signaling. Specific Aim 2 characterizes the effects of L-DOPA on DA release, uptake and diffusion, and on tonic and phasic dopaminergic signaling. Whereas tonic signaling generates dopaminergic tone, phasic signaling produces a transient concentration spike on top of ambient dopamine levels. Phasic signaling is activated by salient stimuli and thought to be important for associative learning. The proposed research is significant, because how and why dopaminergic signaling fails in the severely lesioned striatum is poorly understood. Moreover, L-DOPA is associated with adverse side effects after extended use, apparently due to non-physiological dopamine replacement. However, how L-DOPA acts on dopaminergic signaling is not completely established.